Synthesis of LNA (Locked Nucleic Acid) monomers were first reported by Wengel et al (Singh, S. K.; Nielsen, P., Koshkin, A. A. and Wengel, J. Chem. Commun., 1998, 455; Koshkin, A. A.; Singh, S. K.; Nielsen, P.; Rajwanshi, V. K.; Kumar, R.; Melgaard, M; Olsen, C. E. and Wengel, J., Tetrahedron, 1998, 54, 3607). Depending on which monomer that is prepared, LNA monomer synthesis consists of 15-17 steps. Due to the length of the synthesis it is very important that all steps proceed in the most optimal way. The synthesis steps are optimised on four parameters:                1. Fast reaction time        2. Employing cheap reagents        3. Easy to handle        4. Proceeds in high overall yields        
In the procedures cited in the art the starting material was 1,2:5,6-di-O-isopropylidene-α-D-allofuranose. 1,2:5,6-di-O-isopropylidene-α-D-allofuranose is commercially available (e.g. at Pfanstiel, CAS Number: 2595-05-03). Reducing the cost of the starting material by improving the synthesis is of great value for LNA synthesis.
1,2:5,6-di-O-isopropylidene-α-D-allofuranose is normally prepared from the much cheaper 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose in two steps. The first step is oxidation of the secondary alcohol which is subsequently reduced to provide the allo-configuration. Oxidation of secondary hydroxyl groups to their corresponding carbonyl derivatives with dimethyl sulfoxide (DMSO) and acetic anhydride has been described (Albright J. D. and Goldman L., J. Am. Chem. Soc., 1967, 89:10). The oxidation of alcohols with acetic anhydride-DMSO is described to be a mild oxidative method and giving good yields with sterically hindered hydroxyl groups. They demonstrate in the paper that optimal oxidation is found in the case when ca. 20 times excess of acetic anhydride in relation to the alcohol, is used. All the experiments are performed on alkaloids and on steroids, thus no examples on furanoses are shown.
Also Horton D. and Jewell J. S. (Carbohydrate Res., 1966, 2, 251-260) and Horton, D. and Godman, J. L. (Carbohydrate Res., 1968, 6, 229-232) have used DMSO/Acetic anhydride but they point out that it is important to remove the reagents (DMSO/acetic anhydride) before further reactions and they use either evaporation at reduced pressure or lyophilation to remove the reagents. To carry out the reaction they use an excess of acetic anhydride between 7 and 26 fold.
Baker D. C. et al. (Baker D. C., Horton D. and Tindall C. G., Carbohyd. Res., 1972, 24 192-197) show that acetic anhydride/DMSO oxidation can be applied to 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose and they underline that the method is not effective on large scale. For their large scale synthesis, 0.5 mole 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, they use a complex reaction mixture composed of chloroform, water, potassium metaperiodate, potassium carbonate, and the rare earth metal ruthenium dioxide. After a rather laborious work-up the hydrated ketone is isolated. Thus, they illustrate in this paper that it is not possible to mix the subsequent reduction step with the oxidation step. The overall yield of these two consecutive steps is 64% of crude material. Furthermore, they claim that the DMSO/Acetic anhydride oxidation is not suitable for larger batches>0.5 mole.
Sowa, W. and Thomas, G. H. S., (Can. J. of Chem., 1966, Vol. 44, 836-838) used the DMSO/acetic anhydride oxidation of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose in small scale (10 mmole) using a 20 fold excess of acetic anhydride. The ulose was then reduced providing 1,2:5,6-di-O-isopropylidene-α-D-allofuranose of poor quality, thus the product had to be column purified. Overall this procedure is not suitable for large-scale productions due to the large reagent consumption, two step procedure and the column purification step.
Youssefyeh R. D. et al. (Youssefyeh, R. D., Verhyden, J. P. H., Moffatt, J. G., J. Org. Chem. 1979, 44(8), 1301-1309) employed the DMSO/Acetic anhydride oxidation and subsequent the reduction with sodium borohydride to prepare 1,2-O-isopropylidene-5-O-trityl-4-(trityloxymethyl)-α-D-erythro-pentofuranose from the corresponding threo derivative. Like Baker D. C. et al. they used a large excess of acetic anhydride (10 times) and performed the reaction in small scale (2.13 mmole).
Fuertes C. M. and Cesar M. (Bol. Soc. quim. Peru, 1972. 37(4), 161-74,) prepared 1,2:5,6-di-O-isopropylidene-α-D-allofuranose by a consecutive two step reaction from 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose. However, they used a 13 fold excess of acetic anhydride and allowed the oxidation to proceed for 72 h. The yield in the oxidation step was 60%. The subsequent reduction was performed in 75% yield, thus the overall yield in the sequential reactions was 45%.